“Does the crowd understand?
Is it East versus West
Or man against man?
Can any nation stand alone?”

Burning Heart, by Survivor – Rocky IV

In national politics, the culture wars may pit the coasts against the rest of the country.  In biotech, however, the AI culture war seems to pit the coasts against each other.

Consider this recent LinkedIn post by Chandana Haque, Executive Director of Recursion Pharmaceutical’s startup incubator, Altitude Labs (because they’re based in the mountains of Utah – get it?)

After back-to-back trips to Boston and SF this month, I’m reflecting on some key impressions about the differences between the coasts—especially when it comes to trends in early-stage biotech investing. 🚀

Where did Boston investors get excited? Core biotech: engineering cell machinery, new modalities, and regenerative medicine. This is their strength, and they know it well. But bring up machine learning, and you’ll see a shift; ML just isn’t on the radar for most of New England’s investment crowd, which sticks closely to traditional biotech.

In SF, it’s a different story. AI/ML is seen as critical to understanding complex biology, and it’s almost assumed that every startup will evaluate how ML fits into their approach. SF investors are also intrigued by ADCs, structural biology, and even spatial biology—areas where I found Boston often disengages. The West Coast’s interdisciplinary approach, mixing tech and bio, seems ingrained.

Time will tell how each approach shapes the field, but if you’re traveling coast-to-coast, you’ll feel the difference. What are you seeing?

In short, in the Bay Area, AI is what’s captivating everyone. This passion inevitably finds expression in the contemplation of biotechnology.

The attitude in Boston is, for the most part, rather more reserved. While there are obviously high-profile exceptions, including investors like Flagship Pioneering (which has embraced AI as tightly as any Bay Area fund), and young companies like nference, on balance I think Haque is spot on.

At a recent Boston area healthcare conference (which I can only discuss in general terms because it was held under Chatham House rules), I was struck by the code-switching I observed on a venture panel where a prominent West Coast investor at a firm championing the transformative potential of AI offered a conspicuously understated perspective.

It was not so much the substance but rather the emphasis and affect that was different from what I’ve heard him say in other contexts. Here, speaking to somewhat buttoned-up East Coast business audience, his tone was more guarded, his perspective more grounded, and the changes he foresaw more gradual. 

It’s also possible that in California, even VCs focused on biotech are bankrolled by limited partners who are captivated by the promise of technology and are drawn to VCs and startups that speak the language of radical transformation.

In Boston, the focus tends to be different – not least because of the overwhelming presence in Boston of biologists, physicians and other life science experts whose lived experience has reminded them (as it has reminded me) of the staggering complexity of biology and messiness and inherent humanity of medicine. 

Exhibit A for East Coast early-stage biotech investors (as it has been for many previous years) is the latest iteration of Atlas Venture’s annual Year In Review (watch it here), presented by Bruce Booth, summarizing the state of the biotech industry and ecosystem.

As in previous years, the entire presentation should be required viewing for everyone in the life sciences.

Booth doesn’t spend all that much time on AI, but he calls it out as an area with “great investor interest.” The challenge, he says, is that because of the “incredible amount of buzz and hype” in this space, it’s been “difficult to figure out where the reality is.”

He points out that in 2014, “Recursion said they wanted 100 clinical programs in 10 years” (an aim that I imagine struck tech investors as admirably bold and biotech investors as hopelessly naïve). 

“Unfortunately,” Booth deadpans, “they missed that,” achieving only five clinical programs.

Yet even that represents an important achievement, Booth says, pointing out that “any biotech company that’s just ten years old that has five drugs in the clinic is actually incredibly productive.”

Booth believes AI isn’t just wispy and aspirational. “The reality is there,” he asserts. “AI and machine learning will have targeted impacts up and down the R&D process.”

Preclinical examples he cites include the use of AlphaFold to predict protein structure, and the potential of AI “to predict toxicities or create better routes for manufacturing drugs.”

On the development side of R&D, he suggests AI may contribute to patient selection and enrollment in clinical trials. Moreover, given the established capabilities of large language models, he thinks AI is also likely to provide assistance with regulatory documentation and writing.

But he struggles to find what might be termed West Coast conviction:

“Fundamentally, in the drug R&D space, given the complexity of human biology and the lack of massive datasets, we think that the impact of AI machine learning on R&D is going to be more likely around evolution than revolution. We’re not going to see drug discovery go from a multiyear process to just weeks or days.”

Consequently, Atlas plans to continue its existing (and, Booth says, proven) strategy of leveraging cutting-edge biomedical science to generate promising novel therapeutics.  If AI contributes to the development of a promising target or approach, they’re all for it, but they’re not looking to AI itself as the basis for a platform, nor do they see AI as the transformative unlock for biomedical discovery.

The Atlas view, perhaps not surprisingly, also represents the mindset of most senior pharma R&D executives that I’ve met. 

Yet, this skepticism may start to evolve if — or I suspect, when — AI’s impact is more palpably felt.

As I discussed in my last column, young physicians have quickly embraced an AI clinical app to help guide them through care of individual patients. This should serve as a reminder that while steps enabling change may be imperceptibly small, when change finally comes, it can be rapid. Before long, even big pharmas may find themselves persuaded to embrace their inner Californian.

Meanwhile, leading AI-first biotech companies seem to have become more aware of the essential expertise and implicit knowledge across a range of capabilities that veteran drug developers have accrued and are increasingly recognizing the importance of tapping into this vital experience, found in such abundance along the Charles River.

Perhaps, the next great biotech successfully integrating the approaches represented by the coasts will arise somewhere in the middle.

“If I can change,

And you change,

Everybody can change.”

Rocky Balboa, Rocky IV

In 2011, we were experiencing the ascension of technologies like the cloud and the smartphone.  Apps had become a thing: social network apps like Instagram (the iPhone “App of the Year” in 2011) and Twitter, utility apps like Evernote and Dropbox, navigation apps like Google Maps and Waze, and game apps like Angry Birds.

Yet in medicine, as I wrote that year in Forbes, the “killer app” was…a comparatively old-school e-textbook known as Up-To-Date. The company that created it was founded in 1992.

Written and reviewed by medical experts, Up-To-Date was where everyone in medicine, from earnest med students to overworked residents to seasoned clinicians, turned in the 2010s to find current, reputable information about medical conditions they required to most effectively care for their patients.

Ten years later, in 2021, Up-To-Date was still the go-to app; same for 2022 and 2023.

Yet today, this may be changing.  When a colleague recently mentioned that young doctors now seemed to be using an AI-based resource called “Open Evidence,” I was surprised and somewhat skeptical. 

But when I asked clinical colleagues who work with young doctors every day, I learned that the rumors seemed to be true. 

As UCSF Chief of Medicine Robert Wachter wrote on X, “I think [Open Evidence] is becoming go-to resource for residents. It handles complex case-based prompts, addresses clinical cases holistically, & really good references.”

Harvard clinical colleagues shared similar experiences; one told me the uptake has been “viral,” adding, “I’ve NEVER seen anything like this.”

I know that my academic colleagues will be examining closely both the use and the impact of Open Evidence, with particular emphasis on the effect on patient care. 

Lessons About Technology Adoption

For the biopharma-focused readers of TR, the Open Evidence example serves (or should serve) as a vivid reminder that things don’t change — until suddenly they do. A year ago, everyone was using Up-To-Date; today, many young doctors are embracing Open Evidence.

For emerging technologies, change tends to be driven by “lead users” (to use MIT professor Eric von Hippel’s term) – front-line workers who are focused on solving a pressing problem, and are glad to utilize whatever approach seems most effective. 

When you are a medical resident, your pressing problem is the overwhelming number of things you are dealing with, coming at you from everywhere, all at once. You desperately want to provide the best care to your patients, and you are motivated to turn whatever resource seems most useful. 

That Open Evidence seems to have met this threshold (at least for a number of early-career physicians) is strong testimony to its perceived value. Harried residents, presumably, are not using Open Evidence merely because they are curious about AI, or because there is a department initiative to utilize AI; they’re using it because they see the Open Evidence as the best solution for their problem.  It’s a tool that’s been adopted because of the palpable value it provides.

To these busy young doctors, AI through Open Evidence isn’t a proverbial “solution in search of a problem.” It’s a customized tool addressing their immediate, pressing needs.

There’s an analogy from the field of genetics. For years, I remember hearing endless criticism of physicians for their reluctance to leverage genetics in clinical practice; the urgent need to better educate clinicians in genetics was a familiar, oft-repeated plea.   

Yet, when a genetic diagnostic test (non-invasive prenatal testing, or NIPT) became available that could evaluate reliably specific fetal chromosomal abnormalities from a sample of peripheral blood, and in many cases obviate the need for an amniocentesis, the adoption was both rapid and widespread. Patients, doctors, and payors all seemed to embrace it – because the benefits were palpable.

Implications for AI in Pharma

Which brings us, predictably, back to AI in pharma.

In my last three pieces, I argued that:

• Picking winners consistently in R&D is a vexing challenge.
• Human causal biology, if leveraged rigorously and thoughtfully (eg Vertex, Regeneron) may be able to help.
• While many readers clearly remain skeptical, human causal biology, as leveraged by Vertex and Regeneron, is driving distinct value, and there will be further advantage to be found by thoughtfully leveraging AI.

Readers turned out to be even more skeptical about the application of AI to R&D than they were about the application of human genetics – and impassioned geneticists were often the most critical.   

As one reader (not from the Boston area, incidentally) and genetics enthusiast wrote,

I also think you are far too bullish on AI – I really dislike statements like: “Emerging technologies like AI will help improve scientific understanding and enable better decisions”. We have no idea yet exactly how transformative AI will (or will not) be, and professing with certainty that it will provide value fans the flames of hype that drive so many scam companies to slap a branded faceplate on GPT4 or raise money from VCs with not real vision beyond “AI+$$$$$=awesomeness”.

The AI Chasm in Pharma R&D

I appreciated the candor and perspective, which were certainly familiar, and speak to the sizeable chasm that exists in pharma R&D between AI optimists and skeptics.

On the pro-AI side, there seem to be two largely distinct cohorts: a small group of scientifically sophisticated enthusiasts who are really excited to explore the promise of AI across R&D, and a larger group of “digital transformers.”

The AI-curious scientists, from what I’ve seen, tend to have very little status and organizational clout  in most large pharmas, although there are exceptions (Aviv Regev at Genentech/Roche comes to mind).  More often, at best, they seem to be viewed as adorable (a word I’ve actually heard used by digital transformers).

The mission of the digital transformers is to execute broad corporate initiatives that are launched from the C-suite, driven by management consultants and focused on operational efficiency, typically assessed by near-term process metrics.  These organizational ambitions, invariably emphasizing the infusion of AI across the enterprise, are trumpeted by CEOs at Davos and by big pharma execs at industry conferences like HLTH.

But turning a means into an end can be problematic.  Goodhart’s Law (see here)observes that “When a measure becomes a target, it ceases to be a good measure.”  Similarly, when the mere use of AI becomes the goal, rather than a tool, the result can be a perfusion of performative AI and a dearth of thoughtful application to address the most critical problems a pharma faces: discovering and developing the next original, impactful medicine.

Consequently, it’s understandable why the vast majority of pharma R&D veterans remain generally skeptical about AI in R&D, since it seems to bear all the stigmata of The Next Great Corporate Initiative that needs to be endured in the process of actually doing great science and coming up with impactful new medicines.

The wild hype around AI doesn’t inspire confidence either.  While most startups aspire to lofty goals and tend to launch with brash promises, the extravagant expectations offered by AI startups may be in a league of their own. 

As industry chemist and distinguished “In the Pipeline” blogger Derek Lowe recently reminded readers, in 2014, Recursion Pharma “stated back then that they were going to develop 100 drugs in ten years” – an outlandish proposition that made it difficult for many experienced drug developers to take them seriously.

My concern is that understandable skepticism can easily bleed into reflexive cynicism (I’ve discussed the “cynicism trap” here), that might lead R&D teams to overlook early but authentically promising opportunities that could be truly transformative. 

It’s especially disappointing to me to sense some of this cynicism emanating from geneticists in particular, since at the time that many these geneticists were leaning into the tools and technologies of large-scale genetics, they were on the receiving end of critics who doubted the promise of the approach. 

A representative article, from Stephen S. Hall in Scientific American in 2010, was titled “Revolution Postponed: Why the Human Genome Project Has Been Disappointing.” 

The subheadline to Hall’s piece reads: “The Human Genome Project has failed so far to produce the medical miracles that scientists promised. Biologists are now divided over what, if anything, went wrong—and what needs to happen next.”

Yet over time, and with a huge amount of effort (and financial resources), the value of the Human Genome Project and related endeavors (like the UK Biobank) started (arguably) to prove themselves.  (See, for example, this 2020 article by Richard Gibbs.)

True, genetics has perhaps not lived up to some of the most hopeful early expectations (see the thoughtful comments of Princeton geneticist and computer scientist Olga Troyanskaya here), but by any reasonable estimation, the efforts have proved extraordinarily enabling for science, medicine, and biopharma R&D. 

Bottom Line

I expect AI will ultimately prove similarly transformative, and, when developed wisely and utilized thoughtfully, will be viewed as an essential tool for managing the burgeoning complexity of biopharma R&D. Less certain is when such palpably useful AI tools for advancing R&D science will start to arrive: this year? This decade?   

Like the young doctors now relying on Open Evidence, pharma R&D scientists may soon discover – perhaps sooner than you think – that the use of AI has become second nature for us, part of the fabric of our work, and we may wonder how we managed to survive so long without it.

Two weeks ago, I wrote about how difficult it is for R&D leaders to “pick winners,” despite the enormous incentives to do so.  I explained how we tend to underestimate the role of chance, and overestimate our ability to “domesticate uncertainty,” as Nassim Taleb and I wrote in the Financial Times in 2008. 

Mostly, efforts to systematically improve success rates seem to have come up short.

However, as The Princess Bride (the font of all knowledge, as VC Lisa Suennen explains here) reminds us, “mostly” doesn’t mean “completely.” Occasionally, at least for a period of time, it may be possible to find an “edge” (a term Nate Silver discusses at length in his recent book).  In R&D, this would mean finding an approach, an insight, a team, an organizational structure that might be able to beat the odds consistently.

Earlier this week, I suggested that perhaps Vertex’s approach to human causal biology has provided them just such an edge.  As I emphasized, their secret sauce (if it exists) certainly isn’t the invocation of “human causal biology,” a phrase that, as BioCentury’s Karen Tkach Tuzman recently observed, “is on the lips of research heads and early-stage investors,” and seems to be associated with most every current R&D program.

I argued that Vertex (unlike many competitors) is taking this concept particularly seriously, using it as an ultra-stringent criteria for target and program selection. Unless they can find compelling evidence (usually but not invariably from human genetics) that a particular protein is associated with disease, and also that targeting it is likely to improve the disease, they’re just not interested. 

Vertex’s thesis is that most programs fail because they ultimately don’t generate adequate efficacy in people, and they hope to mitigate this by ensuring that they have a very high degree of confidence in their targets. 

There are obvious tradeoffs with this approach.

For one, they are deliberately not pursuing a range of compelling conditions because they don’t believe they have adequate human causal biology to support such an effort. 

Vertex also strives to remain agnostic about modality, often partnering with platform companies that presumably bring the requisite expertise. Their successful campaign to develop an effective (combination) therapy for most CF patients is a vivid reminder of just how difficult it can be to develop small molecule drugs; deploying emerging technologies is likely to contribute additional degrees of difficulty and uncertainty.

Readers Respond

I anticipated that my two recent pieces about R&D might generate some discussion around what is actually meant by “causal human biology,” and how might this term be defined most usefully if the goal is to increase the odds of successful therapeutic development. 

I also expected some discussion around how computational efforts to quantify causality (as reviewed by Tuzman in BioCentury) might contribute to improved decision-making in pharma, particularly in the context of Vertex’s conviction that what’s required is pivotal insights from human beings, rather than more reductionist approaches that seek to garner primary insight from volumes of data derived from human cell lines cultured in a dish.

I wasn’t surprised that these two articles engaged TR readers given our shared passion for R&D.  What I didn’t expect was the emphasis of the responses, both public (via social media, mostly on Bluesky, which seems to be the new home of BioTwitter) and privately. 

Virtually all of the feedback I received boiled down to: in practice, Vertex isn’t doing anything different than what others are; they do solid science, and perhaps have been a bit lucky, so be careful not to be taken in by a tidy success narrative.

One Bluesky user wrote,

Say you have 200 small/med pharma companies, with 2-10 projects each.  I think just random statistics, if you look over say one 10-year window you would expect one company to have a high success rate and that company would be lauded as highly superior.

Experienced drug hunter Jonathan Rosenblum suggested there was nothing distinctive about how Vertex pursued their sodium channel pain target vs how other companies approached this target, adding,

What I know of their process is – it’s not unique. They haven’t cracked some code that others haven’t. An excellent, science-driven company nonetheless.

Industry veteran and advisor Frank S. David added,

In past 10y I’ve seen *nothing* unique about any pharma co’s R&D decision-making process.  Maybe there were differences in past, but now, they’re all cousins of AZ’s 5Rs….Stories of “better” cos are post hoc rationalizations.  (Note: the “5R” reference is to this paper and subsequent elaboration.)

In addition to noting the concerns about how Vertex’s approach deliberately overlooks important conditions, and is likely to increase risk in some areas (like new modalities) while decreasing risk in others, Frank David makes another, critically important observation:

Interesting to try to predict how much of VRTX R&D decision making is hard wired into co vs dependent on judgement of top execs. I bet a lot of it is the latter. (Ditto Regeneron.) So maybe the lesson for pharma is “hire R&D execs w/ good taste & give them tons of power”? (Good luck with that…)

In other words: perhaps Vertex is a company at the sweet spot with enough resources to try a range of ambitious programs, but small enough so that it’s still guided palpably by strong, smart scientific leadership.

The private feedback I received was essentially a collective eyeroll, as readers emphasized that virtually all biopharma R&D organizations seem to be preaching from the same hymnal, and assert they are pursuing a similar strategy. 

Apparently, it’s only a matter of time before inspirational “Human Causal Biology” posters, suitable for display in your company’s cafeteria, will be available for sale from Successories.

Three Possible Conclusions

Putting it all together, I can see three potential conclusions:

1. Vertex has perhaps been lucky, but actually doesn’t have any durable secret sauce, and has managed to persuade some particularly susceptible investors and colleagues to believe their success narrative. In this view, the confidence exhibited by Vertex leaders today may be similar to that expressed by Pfizer execs in 2018 when they projected 15 blockbusters by 2022 (a pipe dream, as activist investor Starboard has recently highlighted).
2. Vertex is actually doing something different and better, than most, but the “human causal biology” is just the MacGuffin – essentially a plot device to bring together an unusually focused and capable team of physicians and scientist in an productive organizational structure, and with individual leaders capable of delivering unusually good results.
3. Vertex is actually doing something different and better than most, their organizational structure is important, but really it’s their stringent embrace of human causal biology that’s enabling them to have justifiably high confidence in the programs they advance.

And The Answer Is…

In trying to sort this out, it seems relevant to acknowledge several of my own biases. 

I am incredibly partial to compelling science and compelling scientists. I also love the idea of biopharma companies led by science and scientists, rather than managers and metrics. I’ve found it incredibly sad to watch the status of R&D leaders within big pharmas decline over the course of my career, as their inevitable struggles to generate the next blockbuster (and the one after that) has often left them on the defensive, enmeshed with operational efficiency, process metrics and the latest re-org rather than delivering great science.

I’m also especially partial to the power of genetics (which I was drawn to and pursued in graduate school), and to the unique understanding that the study of the whole person provides (see here). When I joined DNAnexus as chief medical officer in 2014, I was motivated, in part, by the knowledge that DNAnexus had worked closely with Regeneron to develop the Regeneron Genetics Center, as I had always admired Regeneron’s George Yancopoulos (see here) and was an enthusiastic supporter of the Center’s ambition to integrate genetics and medical record data to guide scientific discovery. 

In short, I am exquisitely set-up to buy into Vertex’s success narrative, and perhaps this is exactly what’s happening. 

But if it’s true that really no R&D approach is better than any other, and it really is just throwing darts at the genome, then trying not to mess up the execution…I guess this is just a worldview I find myself unable to accept. 

To make a difference, we need to find conviction around something, and I deeply believe we can leverage human causal biology to improve R&D.

I am also probably more optimistic about the opportunities to leverage powerful emerging technologies including AI than current Vertex leadership, although I share Vertex R&D head David Altshuler’s wariness about technology-first approaches.

In addition, I have seen how important organizational context and culture is for R&D.  While nearly all big pharmas describe themselves as science-led, this often isn’t the lived reality. Even at large companies with the best R&D intentions, earnest ambitions tend to dissolve rapidly in a miasma of metrics, process, and power politics.   

In contrast, mid-size companies (as I argued back in 2012, see here) with strong scientific leadership may well be the sweet spot for R&D, as exemplified most recently by Regeneron, Vertex, and Gilead while helmed by chemist John Martin.

Bottom Line: What I Believe (about R&D)

In short: I choose to believe:

• Human causal biology, rigorously applied (which it often is not) can and should guide R&D;
• The right organizational size, structure, and leadership is essential for R&D;
• Emerging technologies like AI will help improve scientific understanding and enable better decisions – after all, it wasn’t all that long ago (1992) when critics explicitly asked if, rather than AI, it was genetics and the Human Genome Project in particular that scientists were unduly fetishizing;
• R&D will inevitably retain a huge element of chance and uncertainty, and success will always require us to be lucky as well as good.

Everybody reading this column knows that biopharma is a difficult business.  Biology is unfathomably complicated and figuring out how to introduce something into the human body that does more good than harm is a fiendishly difficult challenge.

That’s why it’s important to recognize the occasional success. It reminds us what’s possible, and inspires us to think about how to achieve it more often (even as we consciously try to avoid the risk that Cass Sunstein highlights: selecting on the dependent variable and creating tidy post-hoc narratives around rare successes).

We’ll start with what still seems like an unimaginable achievement – the development of a therapy by Vertex Pharmaceuticals that effectively treats the vast majority of patients with cystic fibrosis. 

We’ll then look at this achievement in the context of Vertex’s R&D strategy and consider how they are attempting to challenge (and hopefully defy) the distressingly low odds of drug development, and to demonstrate that, despite the concerns voiced by some wags, that maybe, just maybe, it is possible to “pick winners.”  

Curing CF

First described by Columbia University pathologist Dorothy Hansine Andersen in 1938, cystic fibrosis is a heritable, autosomal recessive disease that affects approximately 40,000 people in the United States and 100,000 people globally. The disease is characterized by thick mucus secretions that logjam the airways in particular.  Afflicted children are beset by constant coughing and lung infections.  Until recently, most endured frequent hospitalizations and constant therapy, and had a median age of survival of around 30 years. 

In 1989, the causative gene, CFTR, was (heroically) cloned by several research groups.  That discovery prompted the next set of questions. Scientists wanted to know what the CFTR gene product actually did, and how disease mutations – including the most common CF mutation, called ΔF508 – affected the protein.

The story of the journey from CF gene to CF therapy, involving both academic researchers and industry scientists, is captured magnificently in a presentation offered by the key participants, as they accepted the 2023 Wiley Prize in Biomedical Science. The introduction and summary, by Richard Lifton, a geneticist and president of Rockefeller University, is superb. 

(See also this excellent 2019 Stat piece by Matthew Herper and Adam Feuerstein.)

Michael Welsh, a physician-scientist at the University of Iowa who shared in the Wiley Prize, told the story of the first CF patient he saw when he was a third-year medical student. 

We go in to see this little girl. She’s probably 7 or 8 years old. And as I watch her, she’s speaking in short sentences. She’s using her accessory muscles, respiration in her neck because she’s short of breath.

And as we talk, we find out that she has doesn’t have a normal life. She can’t go out and do the things that normal kids do. She’s spending much of her day with postural drainage, inhalation of aerosols.  When she coughed, she had this foul sputum. I began to recognize the odor of Pseudomonas aeruginosa in the sputum.

The hard part was when, after seeing her, we went to talk with the faculty, and we learned she might make it to the teens and she was not going to make it out of her teen years. That made a huge impression on me. It stuck with me all my life.

Welsh would go on to focus on the epithelial cells lining the airway, and, with colleagues, show (prior to the identification of the gene for CF) that “there was a problem in the airway with chloride getting out.”

After the CF gene was cloned — a prodigious effort — Welsh demonstrated that defective chloride permeability in cultured cells from patients could be restored with the introduction of the normal (“wildtype”) CF gene, but not with a mutant CF gene. This established a link between the genotype and the disease phenotype.

Welsh also conducted sophisticated patch-clamp studies to demonstrate that the CF gene encoded an ion channel; he was then able to dissect how different components of the channel worked and to understand how mutations disrupted the function. 

For example, some mutations prevented the protein from ever being made; others prevented the protein from folding correctly while still others interfered with proper channel activity.  The most common mutation, ΔF508, exhibited defects in both proper folding and channel opening.

A critical observation Welsh and his colleagues made was that the ΔF508 mutation was temperature sensitive, meaning that while it didn’t function at normal body temperature of 37 degrees Celsius, it did seem to function, somewhat, at lower temperatures, suggesting that if a medicine could duplicate this effect, then function might be restored.

The next set of speakers — Paul Negulescu, Sabine Hadida, and Fredrick Van Goor — described the ensuing stages of the journey — how industry translated this new knowledge of biology into an effective drug.

Negulescu had been working at a San Diego-based startup called Aurora Biosciences. Aurora was founded in 1995 to develop and commercialize assays using reagents like the green fluorescent protein developed by co-founder (and future Nobel Laureate) Roger Y. Tsien. 

In 2000, Aurora received a commitment from the Cystic Fibrosis Foundation to fund $47 million worth of work over five years. A year later, in 2001, Vertex Pharmaceuticals acquired Aurora Biosciences.

As Stat notes, it wasn’t clear if the nascent CF program was initially even on Vertex’s radar. But the funding commitment from the nonprofit CF Foundation contributed to Vertex’s decision to stick with the program rather than cut it.

A self-described “assay guy,” Negulescu approached the challenge of CF by seeking two types of molecules: “correctors,” addressing the protein folding defect, and “potentiators” seeking to restore channel function. The assay also relied on a Tsien reagent that responded to changes in membrane potential (so they could see if channel function was restored), and the temperature sensitive ΔF508 mutations described above.

Building on the initial hits was a chemist named Sabine Hadida, who described the herculean effort required to develop what would become a remarkably effective three-drug regimen.  Development of the first component, a potentiator called ivacaftor, required the synthesis and evaluation of around 800 compounds; first generation correctors such as tezacaftor required synthesis of 3,000 compounds; second generation correctors (e.g. elexacaftor) required upwards of 25,000. 

Subsequent work, as Fredrick Van Goor went on to describe, revealed that these molecules were unusual in several respects; they worked at a distance from the site of the causative mutation, and each bound the CFTR protein at a distinct site.  These interactions all involved parts of the channel that were embedded within the lipid membrane, explaining why the resulting drugs exhibited properties that appeared to “bend” traditional rules.

The clinical impact of the Vertex effort has been extraordinary. The triple combination of ivacaftor, tezacaftor, and elexacaftor (Trikafta) was approved by the FDA in 2019. Patients on the triple-combo treatment are projected to live 72 years (or even longer, if the drug is started when the patient is younger than 18), according to data presented by Van Goor. This compares with an estimated lifespan of 38 years with the best standard of care without these new medicines. These patients also live far healthier lives.

This is a monumental advance for the 90 percent of CF patients who are eligible.  (A different approach will be required for patients unable to manufacture the chloride channel in the first place, and Vertex is pursuing gene therapy-based solutions to address this critical need.)

From Drugs To Strategy

As Stat notes, by 2008, Vertex’s CF efforts had gained enough momentum that, in the words of former Vertex CEO Josh Boger, he “couldn’t stop the program if I tried,” even though it “remained a sideshow” for “management and its investors.”

The CF program could still have been killed when Vertex faced a moment of crisis in the early 2010s.  The company’s sole marketed drug, a hepatitis C therapy marketed as Incivek, was successful at first, then quickly rendered obsolete by more effective competitors.

Things came to a head at a 2012 board meeting led by CEO Jeff Leiden and attended by David Altshuler, a distinguished physician-scientist and geneticist at the Broad Institute who had joined the board of directors.  (He would leave the Broad to join Vertex as head of R&D several years later, in 2015.)

As Leiden saw it, Vertex had three options:

(A) Push forward with hepatitis C;

(B) Try to get acquired by someone who could then sort out next steps; or

(C) Shift the company’s focus to the still relatively early-stage CF program.  

Leiden recommended Option C. The board agreed, and Vertex would go on to deliver remarkable medicines with the power to transform the lives of CF patients (at least those patients eligible for, and with access to these medicines).

The Vertex CF story is actually the (extended) introduction to the R&D strategy topic I want to discuss: has Vertex identified a way to “pick winners?”

For context, we can turn to a fascinating talk Altshuler presented earlier this summer, and available here; many of the same points are summarized here and here, and amplified in this 2023 interview with Endpoints reporter Andrew Dunn, and in this 2024 profile by Michael Gibney.

Altshuler starts his talk by describing the challenges of R&D so familiar to readers of this column, emphasizing our limited understanding of human biology, and the challenge of predicting the impact of interventions. He then outlines Vertex’s R&D strategy, which is to limit the company’s focus, in an unusually rigorous fashion, to “causal human biology” – that is, “targets that have been validated in humans as playing a causal role in human disease.”  He has described this as “targeted conviction.”

This often, but not always, involves human genomics. 

Vertex also strives to be modality agnostic, similar to the concept of matching therapeutic modality to mechanism thoughtfully articulated and passionately advocated by Bristol-Meyer-Squibb CSO Robert Plenge.  Plenge is another champion of the use of causal human biology and a former Altshuler post-doc (see this piece about applying human genetics to drug discovery that Altshuler, Plenge, and former President of Merck Research Laboratories Ed Scolnick penned in 2013). 

The willingness to embrace any relevant modality or target reflects Altshuler’s belief that there isn’t a playbook for drug discovery – rather, “each disease has unique causal human biology, and cracking this biology presents a central challenge in the discovery of a novel therapeutic.” 

Readers will recognize an echo of former Pixar CEO Ed Catmull’s view that there isn’t a formula for successful films, and creative teams have to start from scratch each time.”

Altshuler says Vertex also seeks to “choose programs where there exist or we can invent highly predictive in vitro assays based on primary human cells, and early biomarkers that predict long-term success.”  Finally, he explains, Vertex strives to “select opportunities where the clinical and regulatory path enables efficient assessment of therapeutic potential and to potential approval.”

Altshuler contrasts this approach with many other biopharma companies, who he says tend to organize around a platform (like CRISPR or RNAi), a therapeutic area like cancer or neuroscience, or a “me too” fast follow approach. He suggests this represents commercial strategy more than a science strategy.

The heart of the Vertex approach is focused on data from people, not animal models (or AI models, for that matter).

He contends, “You can have a high success rate if you’re willing to go after human biology. It’s actually the not going after human biology that is the biggest problem in biotherapeutics.”

Altshuler cites not only the clinical success of their CF regimen, but also the recent FDA approval of their ex-vivo gene therapy program to treat sickle cell disease and beta thalassemia (by using CRISPR to excise a repressor of fetal hemoglobin); positive phase 3 data from a pain program strongly informed by human genetic insights; positive phase 2 data in a kidney disease program focused on the inhibition of the APOL1 protein; and encouraging early results from a program driven by my former post-doc mentor Doug Melton focused on transplanting pancreatic beta cells (generated by differentiating stem cells) into patients with type 1 diabetes.   

To be sure, Altshuler is not suggesting Vertex has come up with an infallible formula but argues their approach might be able to significantly improve the probability of success.

I’m not only attracted to Altshuler’s strategy, but (together with Nassim Taleb) have also advocated for it. 

As Taleb and I wrote in the Financial Times in 2008:

The next-generation pharma company will create a lean, agile organisation able to capture, consider and rapidly develop the best scientific ideas in a wide range of disease areas and aggressively guide these towards the clinic. Small market size will not deter their pursuit of promising drugs with a clear and comparatively inexpensive path to clinical development; their ideal portfolio will consist of an extensive collection of such molecules, cheap options that may offer unexpected benefit to patients and provide disproportionately large returns to investors.

Caveats

There are important caveats. FDA approval doesn’t always equate to commercial success and focusing on specialized products at extremely high prices can be tremendously challenging (particularly in the current political environment). That can be the case even if the value to the patient and the healthcare system is exceptional. 

(For now, at least, investors seem to like what they are seeing.  The company’s stock is near its all-time high, and the current market cap is north of $120B – ahead of Gilead Sciences, whose transformative hepatitis C products compelled Vertex to focus elsewhere).

Furthermore, while remaining agnostic about modality does maximize optionality, this approach may underestimate the difficulty of utilizing an emerging technology, where many of the details are still being worked out; presumably Vertex is hedging their risk in these areas by partnering with platform companies like CRISPR Therapeutics and Moderna.

Another key limitation – which Altshuler acknowledges – is that the human causal biology approach (“our quest to go where causal biology demands”), as Vertex applies it, will only work in conditions for which there are compelling data; it’s essentially like looking only where the (causal) light is.  

A Not-So-Secret Sauce?

Even so, the idea of leaning into causal human biology, as Vertex is, seems intuitive and increasingly supported by data. Why doesn’t everyone adopt the Vertex approach? 

Two responses spring to mind. 

First, large pharma organizations are invariably guided by market size projections and are perhaps unlikely to embrace the specialized markets Vertex tends to focus on. 

But this is unlikely the whole answer.

What I really think is happening is something similar to what we’re seeing in tech, where every tech company claims it’s embracing AI, whether it’s OpenAI actually pursuing artificial general intelligence or the many entrepreneur wannabes creating a “glut of scam companies that are little more than wrappers on OpenAI’s GPT tech,” as one Hacker News commenter aptly observed.

In biopharma, as BioCentury astutely noted, and as many readers have probably experienced, “casual human biology” is all the rage. 

“Expectations are rising for researchers to show newly proposed drug targets have a causal role in driving or preventing disease,” writes BioCentury’s Karen Tkach Tuzman, adding that there’s a “mandate to provide proof of causal human biology for novel targets.” 

Tuzman continues,

The phrase is on the lips of research heads and early-stage investors, who use it to mean that a target or pathway plays a role in causing or preventing a human disease, such that modulating it will cause an intended effect in patients. Its rise has paralleled a shift in which the traditional strategy of proposing target hypotheses based on animal studies is taking a back seat to human-first approaches.

What’s more, AI approaches, as BioCentury also notes, increasingly seek to provide computational insight into networks and relationships, quantify causality, and increase probabilities of success. 

In theory, this suggests we’re likely to see a marked increase in translational success, but in practice, what actually seems to be happening across the industry is that “human causal biology” is invoked almost universally to justify any given approach to any given target. 

I don’t think there’s a single program in biopharma R&D that doesn’t have a “causal human biology” narrative to which they can point.

My sense is that Altshuler and Vertex have far more stringent criteria for “causal human biology” than most others, and place particular emphasis on primary insights from human beings rather than what J.S. Haldane called “scraps and fragments” of people (a patient-centric framework Joe Martin, Denny Ausiello, and I advocated here in 2000).  This deliberately high bar may contribute to Vertex’s apparently high success rate. 

By analogy, I’d point to the example of Danaher and its rigorous application of the principle of “kaizen” – continuous improvement. While most every company claims to embrace kaizen, I don’t know of an organization that is more rigorous about it than Danaher, or, over time, more successful. Vertex is as serious about causal human biology as Danaher is about kaizen – a commitment that may be associated with achieving better than expected performance.

Getting Better?

The hope, of course, is that:

• The Vertex approach demonstrates consistent, long-term success in picking winners at a significantly higher rate than average, leading to both clinical and (perhaps underestimated) commercial success.
• Other firms learn to adopt a similarly rigorous approach, and ideally make valuable refinements of their own. (To be sure, Regeneron and Amgen, in particular, have also leaned emphatically into human genetics.  However, as Tuzman writes, the “scarcity of clean genetic signals” raises “a question among players,” namely “how strongly to prioritize genetics relative to other data types.”)
• Most importantly, the science of causal human biology (potentially assisted by AI, as Tuzman describes) advances so that the ability to select and prosecute promising biological targets with Vertex-level rigor and discrimination continues to grow, expanding the group of patients who could benefit from impactful new medicines.